TY - JOUR
T1 - The 3-D conformational shape of N-naphthyl-cyclopenta[d]pyrimidines affects their potency as microtubule targeting agents and their antitumor activity
AU - Xiang, Weiguo
AU - Quadery, Tasdique M.
AU - Hamel, Ernest
AU - Luckett-Chastain, Lerin R.
AU - Ihnat, Michael A.
AU - Mooberry, Susan L.
AU - Gangjee, Aleem
N1 - Funding Information:
The work was supported, in part, by a grant from the National Institutes of Health, National Cancer Institute, R01 CA142868 (AG and SLM), the Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (A.G.) and the Greehey Chair (SLM). This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute, which includes federal funds under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Funding Information:
The work was supported, in part, by a grant from the National Institutes of Health, National Cancer Institute, R01 CA142868 (AG and SLM), the Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (A.G.) and the Greehey Chair (SLM). This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute, which includes federal funds under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Publisher Copyright:
© 2020 Elsevier Ltd
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - A series of methoxy naphthyl substituted cyclopenta[d]pyrimidine compounds, 4–10, were designed and synthesized to study the influence of the 3-D conformation on microtubule depolymerizing and antiproliferative activities. NOESY studies with the N,2-dimethyl-N-(6ʹ-methoxynaphthyl-1ʹ-amino)-cyclopenta[d]pyrimidin-4-amine (4) showed hindered rotation of the naphthyl ring around the cyclopenta[d]pyrimidine scaffold. In contrast, NOESY studies with N,2-dimethyl-N-(5ʹ-methoxynaphthyl-2ʹ-amino)-cyclopenta[d]pyrimidin-4-amine (5) showed free rotation of the naphthyl ring around the cyclopenta[d]pyrimidine scaffold. The rotational flexibility and conformational dissimilarity between 4 and 5 led to a significant difference in biological activities. Compound 4 is inactive while 5 is the most potent in this series with potent microtubule depolymerizing effects and low nanomolar IC50 values in vitro against a variety of cancer cell lines. The ability of 5 to inhibit tumor growth in vivo was investigated in a U251 glioma xenograft model. The results show that 5 had better antitumor effects than the positive control temozolomide and have identified 5 as a potential preclinical candidate for further studies. The influence of conformation on the microtubule depolymerizing and antitumor activity forms the basis for the development of conformation-activity relationships for the cyclopenta[d]pyrimidine class of microtubule targeting agents.
AB - A series of methoxy naphthyl substituted cyclopenta[d]pyrimidine compounds, 4–10, were designed and synthesized to study the influence of the 3-D conformation on microtubule depolymerizing and antiproliferative activities. NOESY studies with the N,2-dimethyl-N-(6ʹ-methoxynaphthyl-1ʹ-amino)-cyclopenta[d]pyrimidin-4-amine (4) showed hindered rotation of the naphthyl ring around the cyclopenta[d]pyrimidine scaffold. In contrast, NOESY studies with N,2-dimethyl-N-(5ʹ-methoxynaphthyl-2ʹ-amino)-cyclopenta[d]pyrimidin-4-amine (5) showed free rotation of the naphthyl ring around the cyclopenta[d]pyrimidine scaffold. The rotational flexibility and conformational dissimilarity between 4 and 5 led to a significant difference in biological activities. Compound 4 is inactive while 5 is the most potent in this series with potent microtubule depolymerizing effects and low nanomolar IC50 values in vitro against a variety of cancer cell lines. The ability of 5 to inhibit tumor growth in vivo was investigated in a U251 glioma xenograft model. The results show that 5 had better antitumor effects than the positive control temozolomide and have identified 5 as a potential preclinical candidate for further studies. The influence of conformation on the microtubule depolymerizing and antitumor activity forms the basis for the development of conformation-activity relationships for the cyclopenta[d]pyrimidine class of microtubule targeting agents.
KW - Antitumor activity
KW - Cyclopenta[d]pyrimidine
KW - Microtubule depolymerizers
KW - Microtubule targeting agents
KW - Structure-activity relationships
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UR - http://www.scopus.com/inward/citedby.url?scp=85097968004&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2020.115887
DO - 10.1016/j.bmc.2020.115887
M3 - Article
C2 - 33310545
AN - SCOPUS:85097968004
VL - 29
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
M1 - 115887
ER -